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S8-3
免疫機轉為標靶的血管炎治療與成大醫院經驗
Immunopathogenesis-based therapy in vasculitis and a monocentric clinical experience
王崇任教授
Chrong-Reen Wang
成大醫院內科部過敏免疫風濕科
Division of Rheumatology and Immunology, Department of Internal Medicine, National Cheng Kung University Hospital |
Vasculitis is the primary manifestation of a disease, or the secondary component of another disease such as hepatitis virus infection and systemic rheumatic disorders. Its pathophysiology involving genetic predisposition, environmental exposures, and immune responses caused by antigenic stimuli. When an offending antigen like drug or an underlying disease like hepatitis B virus infection is recognized in the secondary form, it should be removed or treated as possible. Therapy should be initiated according to the category of primary vasculitis, each with specific and complicated pathogenesis. Immune mechanisms involving in vasculitis include immune complex deposition with activated complement components, T cell-mediated immune injury with granuloma formation, and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophilic degranulation as well as eosinophil-derived direct cytotoxicity, degranulation and cytokines/chemokines release. Based on aforementioned pathophysiology, medium- to high-dose glucocorticoids (GCs) should be started immediately in diseases with irreversible organ/system damage or known high morbidity/mortality. Tapering the dosages of GCs should be attempted after an induction of remission. Conventional immunosuppressants like cyclophosphamide (CYC), azathioprine and methotrexate should be added if there is no adequate response or remission is achieved and maintained with an intolerable regimen of GCs. Furthermore, the selection of an immunosuppressive agent should consider the available therapeutic efficacy, the site and severity of involvement, and the medications-related side effects, especially for the dosages-related cardiotoxicity and the risks of infection, infertility and malignancy in using CYC. Aggressive therapy should be avoided in diseases without irreversible organ/system dysfunction such as idiopathic cutaneous vasculitis. To control the disease activity and sparing the dosages or discontinuing the use of GCs or immunosuppressants, there is an increasing trend in applying biologics and small molecules targeting distinctive pathogenic molecules participating in different vasculitic disorders.
Several biologic agents and small-molecule drugs have received the formal approvals in treating specific vasculitis diseases. Therapeutic indications of rituximab, a B-cell-depleting anti-CD20 monoclonal antibody (mAb), have been approved by the Federal Food and Drug Administration (FDA) and Taiwan for remission induction and follow-up therapy in ANCA-associated vasculitis (AAV), granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), not including eosinophilic granulomatosis with polyangiitis (EGPA) comprising two-third of ANCA-negative cases. IL-5 is responsible for the activation, maturation, survival and recruitment of eosinophils, the central disease pathophysiology in EGPA. An anti-IL-5 mAb, mepolizumab, was approved by the FDA and Taiwan to treat such patients. Furthermore, avacopan, a complement 5a receptor inhibitor blocking the neutrophil activation, received the FDA indication as an adjunctive and add-on treatment to standard therapy for GPA and MPA patients. Tocilizumab, an antiIL6 receptor mAb, has the approval of FDA and Taiwan in treating giant cell arteritis, a medium- and large-sized arteries characteristically involving the temporal artery with IL-6 linked to the disease activity. Behçet’s disease (BD) with leukocytoclastic venulitis as a pathologic process, has received the approval from FDA and Taiwan to treat two underlying manifestations with biologics and small molecules. Apremilast, a small molecule inhibiting phosphodiesterase 4 to reduce the synthesis of cytokines, is used for oral ulcers. Adalimumab (ADA), an anti-tumor necrosis factor mAb, can be prescribed in treating intermediate, posterior or pan-uveitis. In particular, ADA has been approved in patients with intestinal involvement refractory to conventional therapy by Japan and Taiwan. High-dose intravenous immunoglobulin administered early in the disease course is indicated by the FDA and Taiwan for preventing the occurrence of coronary arteritis-induced aneurysm in Kawasaki’s disease.
The Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathways regulate more than 50 cytokine/hormone receptors, many of which have pathogenic roles in vasculitis. Antagonizing a specific JAK can impede more than one cytokine pathway, providing the rationale for using JAK inhibitors (JAKi) as targeted therapy for vasculitic diseases involving multiple cytokines. Takayasu’s arteritis (TAK), mainly affecting the aorta and its major branches, can cause tissue ischemia and organ failure. Biologic agents targeting single cytokine are associated with therapeutic failure in TAK due to its Th1/Th17 pathways-related multi-cytokine pathogenesis. Besides, evidences suggest that JAKi can reduce inflammatory T cells infiltration and resident memory T cells in the vascular wall of TAK. Although there are ongoing randomized controlled trials in TAK patients receiving the treatment of tofacitinib (TOF), a pan-Janus kinase inhibitor suppressing the differentiation of Th1/Th17 cells, results from earlier small-scale studies have demonstrated therapeutic efficacy and clinical safety. Similar to the T-cell responses in TAK, upregulated Th1/Th17 activities have been shown in BD, and clinical observations from case series and reports favored the therapeutic responses of TOF in refractory patients. T cell-associated cytokines are involved in the AAV pathogenesis via activating the JAK/STAT pathways, while an open-label study displayed the effects of TOF treatment. In polyarteritis nodosa, a small-¬ and medium¬-sized necrotizing visceral arteries with pro-inflammatory cytokines levels correlating to disease activity, there was the therapeutic efficacy in using TOF.
In this invited speech, I will discuss the immunopathogenesis-based treatments in miscellaneous vasculitis disorders, and report a monocentric clinical experience in using biologics and small molecules to treat such patients. |
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